Coated citric acid particles



Y 6 r "r' A 2,956,926 Patented Oct. 18, 1960 2,956,926 COATED ClTRICACID PARTICLES Martin Greif, Bronx, N.Y., assignor to American CyanamidCompany, New York, N.Y., a corporation of Maine No Drawing. Filed Sept.23, 1958, Ser. No. 762,690 14 Claims. (Cl. 167-82) This inventionrelates to an improved, free flowing citric acid powder, a method ofpreparing it and pharmaceutical preparations including it.

Citric acid is used extensively for various composi tions,pharmaceutical and otherwise. Thus, for example, citric acid powder maybe admixed with a carbonate or bicarbonate in order to produce aneffervescent composition which may or may not have further constituents,such as aspirin. Another import-ant type of pharmaceutical preparationcontaining citric acid is potentiated tetracyclines. When admixed withcitric acid, the tetracycline is potentiated and better blood levels areobtained. Other uses of citric acid with acid sensitive or moisture,sensitive products are known. A very important class of product is thecitric acid composition in gelatin capsules. For example, citric acidtetracycline compositions are frequently put up in gelatin capsules.

A serious problem has resulted from the citric acid because it attacksmoist gelatin and also reacts With other medicaments; for example, itreduces the effectiveness of tetracyclines on storage by formation ofrelatively inactive anhydro compounds. In the case of effervescencematerial exposed to a humid atmosphere, deterioration also takes place.Another problem, although not so serious, is the strongly acid taste ofordinary citric acid powders which sometimes is disagreeable incompositions containing them.

Attempts to solve the above problem were made by granulating citric acidpowders with hydrophobic barriers. These attempts were not satisfactoryas apparently the coatings were not continuous.

According to the present invention, the problem of coating citric acidparticles so as to render them noncorrosive to gelatin is effected by aplurality of thin coatings of waxy hydrophobic material by alternatelyspraying the waxy material dissolved in a suitable inert volatilesolvent onto sifted citric acid powder in a rotating tablet coating pan,evaporating the solvent, for example by blowing warm air over thestirred particles, and repeating the procedure until the desiredthickness of coating is obtained. It is not known why the presentprocess succeeds whereas the same weight of waxy material applied in asingle coating is not satisfactory. It is possible that if there areoccasional minute discontinuities in the coating, they will not line upin a plurality of thin coatings. It is also possible that successivethin coatings may plug up discontinuities in the first coat and producefinally coats which have no discontinuities or holes. It is not intendedto limit the invention to any particular theory of why the plurality ofthin coatings solved the problem whereas the same amount of wax in asingle coating does not,

Thenumber of coats, which is usually measured by the percentage of thewaxy material based on the citric acid, is not sharply critical and therange thatis useful is not identical for all purposes. Thus, forexample, when the problem is to prevent corrosion of gelatin capsules, anumber of coats which put less than 5% of waxy material on the citricacid are not suflicient. 5% represents about the irreducible minimumwhich can be used in a gelatin capsule. With 5%, some pitting does takeplace but there was no disintegration to an extent which would rendercapsules unuseable. When the the invention, but as they have nopractical advantage over 20%, they will normally not be used.

When a coated citric acid powder is used in compositions containingtetracyclines, the requirements are somewhat more severe. With 6% ofwax, there is no useful protection against formation ofanhydrotetracycline. The amount formed is slightly reduced, but is stillso high as to present no real advantage. A worthwhile protection isobtained with about 9% of wax which reduces anhydrotetracyclineformation to less than half,

and with 20% wax, the protection is complete. Therefore, forcompositions containing tetracycline, the range is narrower than withgelatin capsules where the corrosive effect on gelatin is the onlyfactor and may be con sidered as-ranging from 9% to 20%.

The particular waxy material is not too sharply critical but it should,in general, involve a major portion of a glyceride wax, such as glycerylmonostearate or distearate, with a minor proportion of a plasticizingwax, such as beeswax. For practical purposes, proportions of the orderof magnitude of and 10% give optimum results. The particular combinationof high melting fat and Wax described above is not the only one that canbe used. In fact, in general high melting fats can be used with eitherbeeswax or waxy higher alcohols. Carnauba wax is not satisfactory alone,but in blends it permits an accurate degree of hardening.

The solvent to be used presents primarily a physical problem. Of course,it must be inert to citric acid. Also, it must not be highly toxic or atleast any minute residue left should not be highly toxic since thecitric acid is normally ingested. Volatility is important.Theoretically, even" only moderately volatile solvents for the waxcomposition could be used. However, it is not practical to dry orevaporate the solvent at an excessive temperature. If the temperature istoo high, the wax will soften to the extent that coated particles of thecitric acid will stick together and they will no longer be free flowing.For practical purposes, it is desirable to effect the drying attemperatures not substantially in excess of 50 C. It should be notedthat the temperature of the 'Warm air used in drying may be s omewh athigher than the actual temperature on the surface of the particles, asthe evaporation of the solvent exerts a cooling effect. It is true thatif there is sufficient time, even a fairly high boiling solvent could beevaporated at the moderate temperature. However, the time would beexcessive and therefore it is desirable to use an inert solvent whichhas a boiling point not greatly in excess of C. and preferably below1009 C. A simple, ch eap and very satisfactory solvent 1,1,1 tricliloroethan'e, which is inert, boils at about 74 urally, the solutionmust be thin enough 'so'that it can be satisfactorily. sprayed to form athin coating, but this is a purel y physic'alfproblem and represents nocritical facto'n' Theiiivention will bedescribed inconn'ectiori with thefollowing specific examples in which the effect of a coated citric acidon gelatin and other medicaments is illustrated as well as the processof coating. The examples are typical only and do not limit the inventionto the use of a coated citric acid in the particular formulation setforth. The parts are by weight unless otherwise specified.

Example 1 Citric acid powder sifted through No. 30 mesh screen is placedin a conventional rotating tablet coating plan and sprayed with a 30%solution of a wax mixture comprising 9 parts glyceryl monostearate and 1part beeswax in 1,1,l-trichlroethane. After a thin coating, the spray isinterrupted and warm air is blown over the swirling coated citric acidparticles. As soon as the solvent has been substantially evaporated,another spraying cycle follows and this is repeated until 7.5% of waxcoating was achieved. Gelatin capsules are filled with the above coatedcitric acid after the latter had been passed through a No. 30 meshscreen. A control run of soft gelatin capsules of the same gelatincomposition were likewise filled with uncoated citric acid. The capsuleswere sealed in air-tight bottles and stored for 24 hours.

At the end of the 24 hours, the control capsules showed gelatin whichwas pitted, mottled and partially liquefied. The capsules with thecoated citric acid were generally unaffected.

The procedure was repeated but both batches of capsules were carefullydried after filling. After 24 hours, the controls had leaked somesolution, were pitted, mottled and chewed up and, of course, the coatedcitric acid capsules were unaflected.

Example 2 The citric acid, coated as described in Example 1, was mixedwith an equal proportion of tetracycline hydrochloride. Controls wereprepared using uncoated citric acid. On storing, the gelatin capsulescontaining uncoated citric acid were mottled and pitted and wereunsuitable for sale.

The gelatin capsules with the coated citric acid were unalfected andwere saleable.

Example 3 The procedure of Example 1 was repeated with difierent amountsof wax coating, namely, 6%, 10% and 20% by weight. Citric acid with eachthickness of coating was mixed with an equal amount of tetracyclinehydrochloride and incorporated into soft gelatin capsules. The capsulesWere then set in a -10% relative humidity atmosphere to dry for about 24hours, washed with isopropanol in a conventional manner and air dried.They were then bottled and stored for about 7 months. On opening, therewere no mottled capsules. Some of the capsules containing 6% wax showeda little evidence of pitting inside the capsule when cut open. All,however, were saleable.

Example 4 The procedure of Example 3 was followed in order to test theeffect of the citric acid on tetracycline and a control was also madeup. The formulations were then stored for 3 days and assayed foranhydrotetracycline formation. The results appear in the followingtable:

It will be noted that even tetracycline HCl alone shows a small amount,1.3 milligrams of anhydrotetracycline. The figures for the variousmixtures with citric acid must therefore be compared with this figure.In other words, 1.3 milligrams of anhydrotetracycline must be subtractedfrom each figure in order to get the net increase. It will be noted thatwhile there was some reduction in anhydrotetracycline formation withapproximately 6% wax coating, namely about 21%, there was still anextensive formation of anhydrotetracycline and therefore this degree ofcoating is not quite sufficient. Coating with a little more than 9% waxshowed a reduction of about 41% and is of practical significance. The20% coating showed no anhydrotetracycline formation at all over andabove that which is present in the base to start with.

I claim:

1. Free flowing powdered citric acid having a particle size at least asfine as 30 mesh having a plurality of thin coats of a predominantlyglyceride wax, the coats being suflicient in number so that the totalwax coating is in excess of 5%.

2. A gelatin capsule filled with a free flowing powder compositioncomprising the free flowing citric acid of claim 1.

3. A product according to claim 1 in predominantly glycerylmonostearate.

4. A gelatin capsule filled with powdered material comprising the coatedcitric acid of claim 3.

5. Free flowing powdered citric acid having a particle size at least asfine as 30 mesh having a plurality of thin coats of a predominantlyglyceride wax, the coats being sulficient in number so that the totalwax coating" is in excess of 9%.

6. A gelatin capsule filled with a mixture of free flowing tetracyclineHCl and coated citric acid powder of claim 5.

7. A product according to claim 5 in predominantly glycerylmonostearate.

8. A gelatin capsule filled with a mixture of tetracycline HCl powderand coated citric acid powder according to claim 7.

9. A process of coating citric acid powder having a particle size atleast as fine as 30 mesh which comprises agitating the powder, sprayingit while agitated with a solution of a wax in a volatile inert solvent,evaporating the solvent and repeating until suificient coatings areformed so that the wax coating is at least 5% by weight of the citricacid particle.

10. A process according to claim 9 in which the wax is predominantlyglyceryl monostearate.

11. A process according to claim 10 vent is 1,1,1-trichloroethane.

12. A process of coating citric acid powder having a particle size atleast as fine as 30 mesh which comprises agitating the powder, sprayingit while agitated .witha solution of a wax in a volatile inert solvent,evaporating the solvent and repeating until sufficient coatings areformed so that the wax coating is at least 9% by weight of the citricacid particle.

13. A process according to claim 12 in which the Wax is predominantlyglyceryl monostearate.

14. A process according to claim 13 in which the solvent is1,1,l,-trichloroethane.

which the wax is which the'wax is in which the sol- References Cited inthe file of this patent UNITED STATES PATENTS

1. FREE FLOWING POWDERED CITRIC ACID HAVING A PARTICLE SIZE AT LEAST ASFINE AS 30 MESH HAVING A PLURALITY OF THIN COATS OF A PREDOMINANTLYGLYCERIDE WAX, THE COATS BEING SUFFICIENT IN NUMBER SO THAT THE TOTALWAX COATING IS IN EXCESS OF 5%.
 2. A GELATIN CAPSULE FILLED WITH A FREEFLOWING POWDER COMPOSITION COMPRISING THE FREE FLOWING CITRIC ACID OFCLAIM 1.